1. Field
Provided are hyaluronic acid conjugates, complexes, and compositions useful for nucleic acid delivery. Additionally, the present invention relates to methods for nucleic acid delivery using hyaluronic acid conjugates, complexes, and compositions.
2. Description of the Related Art
Small interfering ribonucleic acid-based (siRNA-based) therapeutics are actively being developed worldwide, and are used for the treatment of incurable diseases such as Alzheimer's disease, diabetes, obesity, rheumatoid arthritis, Parkinson's disease, hepatitis type B, hepatitis type C, AIDS, cancer, and the like. siRNA-based therapeutics are designed to regulate the expression mechanism of their target genes by destroying specific messenger ribonucleic acid (mRNA) to cease the transcription and translation of target genes. However, siRNA is susceptible to degradation by various enzymes that are abundantly found in the blood plasma of living organisms (e.g., mammals), within a short time after the siRNA is exposed to blood. As a result, when siRNAs are injected intravenously, most siRNAs are degraded before they are able to perform their function unless they are biochemically protected. In addition, siRNAs are likely to be recognized as an antigen or a foreign matter in vivo, which may induce an undesirable immune response. Furthermore, siRNA may affect a gene locus other than a target gene, provoking cross-hybridization with irrelevant gene sequences. Accordingly, active research has been conducted to develop new siRNA formulations with enhanced stability and minimized undesirable side effects. Particular attention has been paid to various drug delivery systems including nanoparticles, micelles, liposomes, polymer complexes, etc. to increase in vivo stability of siRNA while minimizing the undesirable side effects of siRNA drugs. Non-viral siRNA drug delivery systems that have been developed attempt to increase the stability of siRNA. These systems bind siRNA to the surface of positively charged liposomes to stabilize the siRNA in an effort to prevent the rapid destruction of siRNA, which is common when isiRNA is administered alone.
Alternative strategies combine siRNA with a positively charged, amphiphilic polymer through electrostatic interaction to form an electrically neutral nanoparticle which is improved in targeting ability, to effectively deliver siRNA to a target. Cancer, representative of the diseases to which siRNA therapy is applicable, is characterized by active cell division, requiring a massive supply of nutrients and oxygen, compared to normal tissues. Cancer tissues form vessels to meet these demanding nutrient and oxygen requirements. The walls of the newly formed vessels are structurally irregular and flimsy. In addition, cancer tissues experience significantly lower drainage through the lymphatic duct than compared to normal tissues. As a result, polymers can be retained longer in cancer tissues than other tissues or organs. To take advantage of the enhanced permeability and retention (EPR) characteristics of cancer, amphiphilic nanoparticle-siRNA complexes have recently been suggested for effective delivery of siRNA.
Nonetheless, there still is a need for a delivery system by which nucleic acids can be delivered at greater efficiency with higher stability to a subject.